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Severe stress switches CRF action in the nucleus accumbens from appetitive to aversive.

Lemos JC, Wanat MJ, Smith JS, Reyes BA, Hollon NG, Van Bockstaele EJ, Chavkin C, Phillips PE - Nature (2012)

Bottom Line: Remarkably, severe-stress exposure completely abolished this effect without recovery for at least 90 days.This loss of CRF's capacity to regulate dopamine release in the nucleus accumbens is accompanied by a switch in the reaction to CRF from appetitive to aversive, indicating a diametric change in the emotional response to acute stressors.Thus, the current findings offer a biological substrate for the switch in affect which is central to stress-induced depressive disorders.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington 98195, USA.

ABSTRACT
Stressors motivate an array of adaptive responses ranging from 'fight or flight' to an internal urgency signal facilitating long-term goals. However, traumatic or chronic uncontrollable stress promotes the onset of major depressive disorder, in which acute stressors lose their motivational properties and are perceived as insurmountable impediments. Consequently, stress-induced depression is a debilitating human condition characterized by an affective shift from engagement of the environment to withdrawal. An emerging neurobiological substrate of depression and associated pathology is the nucleus accumbens, a region with the capacity to mediate a diverse range of stress responses by interfacing limbic, cognitive and motor circuitry. Here we report that corticotropin-releasing factor (CRF), a neuropeptide released in response to acute stressors and other arousing environmental stimuli, acts in the nucleus accumbens of naive mice to increase dopamine release through coactivation of the receptors CRFR1 and CRFR2. Remarkably, severe-stress exposure completely abolished this effect without recovery for at least 90 days. This loss of CRF's capacity to regulate dopamine release in the nucleus accumbens is accompanied by a switch in the reaction to CRF from appetitive to aversive, indicating a diametric change in the emotional response to acute stressors. Thus, the current findings offer a biological substrate for the switch in affect which is central to stress-induced depressive disorders.

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Stress exposure abolishes the CRF mediated increase in evoked dopamine release and subsequent appetitive behaviorsa, Effect of CRF on dopamine release in naïve mice (blue) and following swim stress (red), n = 8-18 (left), and in animals that were pretreated with the glucocorticoid-receptor antagonist, RU 486 (30 mg/kg, i.p.) or its vehicle prior to stress, n= 6-10 (right). b, Mean (+ s.e.m) place preferences for intra-accumbensCRF in naïve (blue) and stress exposed mice (red), n = 6-8 (left) and representative activity traces (right). c, Difference in the increased center time during presentation of novel object between vehicle and CRF-receptor antagonism in naïve (blue) and 7-day post-stress (red) animals, n = 9-10. Data on bar graphs are mean + s.e.m.; ns p > 0.05, * p < 0.05, ** p < 0.01; § p < 0.05, §§ p < 0.01 for interaction.
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Figure 4: Stress exposure abolishes the CRF mediated increase in evoked dopamine release and subsequent appetitive behaviorsa, Effect of CRF on dopamine release in naïve mice (blue) and following swim stress (red), n = 8-18 (left), and in animals that were pretreated with the glucocorticoid-receptor antagonist, RU 486 (30 mg/kg, i.p.) or its vehicle prior to stress, n= 6-10 (right). b, Mean (+ s.e.m) place preferences for intra-accumbensCRF in naïve (blue) and stress exposed mice (red), n = 6-8 (left) and representative activity traces (right). c, Difference in the increased center time during presentation of novel object between vehicle and CRF-receptor antagonism in naïve (blue) and 7-day post-stress (red) animals, n = 9-10. Data on bar graphs are mean + s.e.m.; ns p > 0.05, * p < 0.05, ** p < 0.01; § p < 0.05, §§ p < 0.01 for interaction.

Mentions: Exposure to severe or chronic stress can produce profound alterations in normal stress signaling that can be detrimental to physical and mental health, predisposing individuals to depression19. To model this phenomenon, we employed a modified Porsolt paradigm in which mice are exposed to two days of repeated swim stress. Animals were placed in a vessel of water (29.0 - 31.0 °C) for 15 minutes followed by four additional 6-minute swim sessions (separated by 6-minute recovery periods) 24 hours later. This protocol has been shown to produce escalating immobility across sessions indicating a depression-like phenotype20. We prepared coronal slices of the nucleus accumbens from these animals thirty minutes after the final stress exposure and found that the ability for CRF to potentiate dopamine release was completely abolished (stress exposure by drug, F4,116 = 12.61, p < 0.001 two-way ANOVA, Fig. 4a). Notably, we established that this change in the ability of CRF to regulate dopamine release was not a generalized change in stress-related peptide signaling as the effect of a kappa-opioid agonist to reduce dopamine release was unaffected by the two-day stress-exposure paradigm (Supplementary Fig. 9). Therefore, these data demonstrate that severe stress selectively abolishes CRF’s ability to modulate dopamine release in the nucleus accumbens. Surprisingly, there was no recovery of the action of CRF on dopamine release in the nucleus accumbens 7, 30 or even 90 days after stress exposure (stress exposure by drug, F4,116 = 4.852, p < 0.01, two-way ANOVA; Fig. 4a). This time period is consistent with the protracted course of stress-induced depressive disorders21, and indeed, a depression-like phenotype was maintained across this 90-day post-stress period as assessed by swim immobility (Supplementary Fig. 10). Importantly, the loss of the CRF response was neither due to a baseline change in evoked dopamine release (Supplementary Fig. 11) nor simply an age-related phenomenon (Supplementary Fig. 12). Therefore, we have demonstrated that severe stress produces a persistent dysregulation of CRF-dopamine interactions that normally produce a positive affective state.


Severe stress switches CRF action in the nucleus accumbens from appetitive to aversive.

Lemos JC, Wanat MJ, Smith JS, Reyes BA, Hollon NG, Van Bockstaele EJ, Chavkin C, Phillips PE - Nature (2012)

Stress exposure abolishes the CRF mediated increase in evoked dopamine release and subsequent appetitive behaviorsa, Effect of CRF on dopamine release in naïve mice (blue) and following swim stress (red), n = 8-18 (left), and in animals that were pretreated with the glucocorticoid-receptor antagonist, RU 486 (30 mg/kg, i.p.) or its vehicle prior to stress, n= 6-10 (right). b, Mean (+ s.e.m) place preferences for intra-accumbensCRF in naïve (blue) and stress exposed mice (red), n = 6-8 (left) and representative activity traces (right). c, Difference in the increased center time during presentation of novel object between vehicle and CRF-receptor antagonism in naïve (blue) and 7-day post-stress (red) animals, n = 9-10. Data on bar graphs are mean + s.e.m.; ns p > 0.05, * p < 0.05, ** p < 0.01; § p < 0.05, §§ p < 0.01 for interaction.
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Figure 4: Stress exposure abolishes the CRF mediated increase in evoked dopamine release and subsequent appetitive behaviorsa, Effect of CRF on dopamine release in naïve mice (blue) and following swim stress (red), n = 8-18 (left), and in animals that were pretreated with the glucocorticoid-receptor antagonist, RU 486 (30 mg/kg, i.p.) or its vehicle prior to stress, n= 6-10 (right). b, Mean (+ s.e.m) place preferences for intra-accumbensCRF in naïve (blue) and stress exposed mice (red), n = 6-8 (left) and representative activity traces (right). c, Difference in the increased center time during presentation of novel object between vehicle and CRF-receptor antagonism in naïve (blue) and 7-day post-stress (red) animals, n = 9-10. Data on bar graphs are mean + s.e.m.; ns p > 0.05, * p < 0.05, ** p < 0.01; § p < 0.05, §§ p < 0.01 for interaction.
Mentions: Exposure to severe or chronic stress can produce profound alterations in normal stress signaling that can be detrimental to physical and mental health, predisposing individuals to depression19. To model this phenomenon, we employed a modified Porsolt paradigm in which mice are exposed to two days of repeated swim stress. Animals were placed in a vessel of water (29.0 - 31.0 °C) for 15 minutes followed by four additional 6-minute swim sessions (separated by 6-minute recovery periods) 24 hours later. This protocol has been shown to produce escalating immobility across sessions indicating a depression-like phenotype20. We prepared coronal slices of the nucleus accumbens from these animals thirty minutes after the final stress exposure and found that the ability for CRF to potentiate dopamine release was completely abolished (stress exposure by drug, F4,116 = 12.61, p < 0.001 two-way ANOVA, Fig. 4a). Notably, we established that this change in the ability of CRF to regulate dopamine release was not a generalized change in stress-related peptide signaling as the effect of a kappa-opioid agonist to reduce dopamine release was unaffected by the two-day stress-exposure paradigm (Supplementary Fig. 9). Therefore, these data demonstrate that severe stress selectively abolishes CRF’s ability to modulate dopamine release in the nucleus accumbens. Surprisingly, there was no recovery of the action of CRF on dopamine release in the nucleus accumbens 7, 30 or even 90 days after stress exposure (stress exposure by drug, F4,116 = 4.852, p < 0.01, two-way ANOVA; Fig. 4a). This time period is consistent with the protracted course of stress-induced depressive disorders21, and indeed, a depression-like phenotype was maintained across this 90-day post-stress period as assessed by swim immobility (Supplementary Fig. 10). Importantly, the loss of the CRF response was neither due to a baseline change in evoked dopamine release (Supplementary Fig. 11) nor simply an age-related phenomenon (Supplementary Fig. 12). Therefore, we have demonstrated that severe stress produces a persistent dysregulation of CRF-dopamine interactions that normally produce a positive affective state.

Bottom Line: Remarkably, severe-stress exposure completely abolished this effect without recovery for at least 90 days.This loss of CRF's capacity to regulate dopamine release in the nucleus accumbens is accompanied by a switch in the reaction to CRF from appetitive to aversive, indicating a diametric change in the emotional response to acute stressors.Thus, the current findings offer a biological substrate for the switch in affect which is central to stress-induced depressive disorders.

View Article: PubMed Central - PubMed

Affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington 98195, USA.

ABSTRACT
Stressors motivate an array of adaptive responses ranging from 'fight or flight' to an internal urgency signal facilitating long-term goals. However, traumatic or chronic uncontrollable stress promotes the onset of major depressive disorder, in which acute stressors lose their motivational properties and are perceived as insurmountable impediments. Consequently, stress-induced depression is a debilitating human condition characterized by an affective shift from engagement of the environment to withdrawal. An emerging neurobiological substrate of depression and associated pathology is the nucleus accumbens, a region with the capacity to mediate a diverse range of stress responses by interfacing limbic, cognitive and motor circuitry. Here we report that corticotropin-releasing factor (CRF), a neuropeptide released in response to acute stressors and other arousing environmental stimuli, acts in the nucleus accumbens of naive mice to increase dopamine release through coactivation of the receptors CRFR1 and CRFR2. Remarkably, severe-stress exposure completely abolished this effect without recovery for at least 90 days. This loss of CRF's capacity to regulate dopamine release in the nucleus accumbens is accompanied by a switch in the reaction to CRF from appetitive to aversive, indicating a diametric change in the emotional response to acute stressors. Thus, the current findings offer a biological substrate for the switch in affect which is central to stress-induced depressive disorders.

Show MeSH
Related in: MedlinePlus